Artemisinin Resistance Mechanisms in Plasmodium falciparum Malaria

Artemisinin derivatives remain the most rapid‐acting antimalarials for treating Plasmodium falciparum infection. Resistance has emerged through multiple interconnected mechanisms. Central among these are non‐synonymous mutations in the Kelch13 propeller region, which slow parasite clearance by altering ring-stage susceptibility. Artemisinin exposure can also induce a reversible dormant or quiescent state in early ring forms, allowing parasites to survive transient drug pressure. Resistance to partner drugs in artemisinin combination therapies (ACTs) further compromises treatment efficacy. Amplification of plasmepsin 2-3 genes and novel mutations in the chloroquine resistance transporter (pfcrt) reduce piperaquine and related drug sensitivity, while copy number variations of mdr1 and mutations in crt contribute to mefloquine and lumefantrine failures. These genetic adaptations have arisen independently across Southeast Asia and, more recently, in Africa, challenging global elimination efforts. Integrating molecular surveillance with adaptive drug policies—such as multiple first-line therapies and extended dosing schedules—offers a pathway to contain resistance and guide development of next‐generation antimalarials.

Research from Nature Portfolio

Spatial modelling of pfkelch13 R561H emergence in Rwanda has demonstrated that deploying multiple first-line therapies or extending ACT courses can reduce treatment failures and delay resistance spread compared with standard three-day regimens. In Ethiopia, deep sequencing of parasite genomes revealed expansion of pfkelch13 622I mutants, often co-occurring with pfhrp2/3 deletions, indicating simultaneous drug and diagnostic resistance and underlining the need for integrated surveillance. Laboratory studies of artemisinin-induced dormant stages in P. falciparum ring forms characterized a five-day maturation process culminating in a quiescent phenotype with altered transcriptomes, increased DNA‐repair activity and enhanced resilience to antimalarial drugs, emphasising the role of cellular dormancy in treatment failure and informing strategies for targeting metabolically arrested parasites.

Artemisinin Resistance Mechanisms in Plasmodium falciparum Malaria publication trend

The graph below shows the total number of articles in artemisinin resistance mechanisms in plasmodium falciparum malaria across all publications each year (not limited to Nature Index journals).

Technical terms

Artemisinin combination therapy (ACT): Regimens combining an artemisinin derivative with a partner drug to enhance parasite kill rate and delay resistance.

Kelch13 propeller mutation: Non-synonymous changes in the propeller domain of the PfKelch13 protein that slow parasite clearance following artemisinin exposure.

Dormancy/quiescence: Reversible, non-replicative state adopted by ring-stage parasites under drug pressure, characterised by slowed metabolism and increased survival.

Plasmepsin 2-3 amplification: Increased copy numbers of haemoglobin-digesting protease genes that confer reduced piperaquine sensitivity.

pfcrt (chloroquine resistance transporter): Membrane transporter in P. falciparum whose mutations alter susceptibility to quinoline and piperaquine drugs.

Multiple first-line therapies (MFT): Strategy deploying several first-line antimalarial regimens concurrently to diversify drug pressure and limit resistance selection.

References

1. Modeling policy interventions for slowing the spread of artemisinin-resistant pfkelch R561H mutations in Rwanda. Nature Medicine (2023).
2. Plasmodium falciparum resistant to artemisinin and diagnostics have emerged in Ethiopia. Nature Microbiology (2023).
3. The artemisinin-induced dormant stages of Plasmodium falciparum exhibit hallmarks of cellular quiescence/senescence and drug resilience. Nature Communications (2024).
4. A surrogate marker of piperaquine-resistant Plasmodium falciparum malaria: a phenotype–genotype association study. The Lancet Infectious Diseases (2016).
5. Determinants of dihydroartemisinin-piperaquine treatment failure in Plasmodium falciparum malaria in Cambodia, Thailand, and Vietnam: a prospective clinical, pharmacological, and genetic study. The Lancet Infectious Diseases (2019).
6. Association of mutations in the Plasmodium falciparum Kelch13 gene (Pf3D7_1343700) with parasite clearance rates after artemisinin-based treatments—a WWARN individual patient data meta-analysis. BMC Medicine (2019).
7. Evolution and expansion of multidrug-resistant malaria in southeast Asia: a genomic epidemiology study. The Lancet Infectious Diseases (2019).
8. Emerging Southeast Asian PfCRT mutations confer Plasmodium falciparum resistance to the first-line antimalarial piperaquine. Nature Communications (2018).